PROJECT SUMMARY: NEUROBEHAVIORAL CORE 3 We are proposing the creation of a research program entitled, ?Increasing the therapeutic index of brain tumor treatment through innovative FLASH radiotherapy (FLASH-RT), focused on translating a novel irradiation modality rapidly into the clinic. The overall hypothesis to be tested is whether radiation delivered at ultra high dose rates (compared to the much lower dose rates used in current clinical practice) can significantly ameliorate normal tissue complications while maintaining acceptable if not improved tumor control. To test this hypothesis, the program will deploy a comprehensive series of preclinical studies that will critically evaluate tumor control, neurocognitive outcomes and resultant radiation injury to the brain following FLASH-RT and conventional dose rate irradiation. Collectively, these studies will generate the requisite data sets required for the rapid translation of the novel FLASH irradiation platform to the clinical scenario. Preclinical studies in mice assessing orthotopic tumor control, cognition, neuronal and vascular structural plasticity, immune-modulation and oxygen dependent mechanisms of radiation injury are coupled with a clinical trial in GBM dog patients to inform the oncologists of the potential benefits of this potentially paradigm shifting technology. The objectives of this program project will be facilitated by the activities conducted by the dosimetry/physics core (Core 2) and the Neurobehavioral Core (Core 3). The primary function of Core 3 will be to provide a uniform behavioral testing platform in which animals irradiated at the other performance sites (CHUV, Stanford, Indiana) will be shipped to and tested at UCI. The neurobehavioral core at UCI is able to accommodate the neurocognitive testing objectives required for animals subjected to single fraction, and multifraction FLASH and conventional dose rate irradiation protocols as described in Projects 1, 2 and 4. This will be accomplished through a unifying neurobehavioral testing platform, designed to determine how specified irradiation protocols impact sensitive paradigms of learning, memory and mood, multifaceted endpoints critical to therapeutic outcome. Core 3 will be led by Dr. Chares Limoli, renowned expert in analyzing the impact of multiple radiation types, paradigms and cancer treatment regimens on cognition, and operated by neurobiologist Munjal Acharya and radiobiologist Janet Baulch. This team has more than 12 years of behavioral testing experience and has been recognized for identifying some of the first stem cell, exosome, pharmacologic and genetic based strategies for resolving cancer treatment-induced cognitive dysfunction. In sum, Core 3 will serve as an integrative hub to ensure experimental consistency across Projects 1, 2 & 4. More broadly, Core 3 will provide a major service to the radiation oncology research field by promoting the acquisition and dissemination of data relevant to a potentially transformative branch of radiation oncology and cancer treatment in general.